Journal of Cardiology 75 (2020) 34–41

Original article

Prognosis and risk stratification in cardiac sarcoidosis patients withpreserved left ventricular ejection fraction

Takahiko Chiba (MD)a, Makoto Nakano (MD, PhD)a,*, Yuhi Hasebe (MD, PhD)a,Yoshitaka Kimura (MD)a, Kyoshiro Fukasawa (MD)a, Keita Miki (MD)a,Susumu Morosawa (MD)a, Kentaro Takanami (MD, PhD)b, Hideki Ota (MD, PhD)b,Koji Fukuda (MD, PhD, FJCC)c, Hiroaki Shimokawa (MD, PhD, FJCC)a

aDepartment of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanbDepartment of Diagnostic Radiology, Tohoku University Graduate School of Medicine, Sendai, JapancDepartment of Cardiovascular Medicine, International University Health and Welfare, Nasushiobara, Japan

A R T I C L E I N F O

Article history:Received 4 October 2018Received in revised form 25 March 2019Accepted 25 April 2019Available online 2 July 2019

Keywords:Cardiac sarcoidosisEjection fractionRight ventricular pacingMyocardial damage

A B S T R A C T

Background: Although recent reports showed that left ventricular ejection fraction (LVEF) is a prognosticfactor in patients with cardiac sarcoidosis (CS), advances in diagnostic imaging have enabled us to detectCS patients with preserved LVEF in the early stage of the disorder. In the present study, we examined theprognosis and risk stratification in CS patients with preserved LVEF.Methods and results: We retrospectively examined 91 consecutive CS patients at our hospital fromOctober 1998 to December 2015 (age, 57 � 11 years; male/female, 25/66) for the relationship betweenLVEF and major adverse cardiac events (MACE), including ventricular tachycardia and fibrillation (VT/VF),heart failure (HF) admission, complete atrioventricular block, and all-cause death. CS patients withpreserved LVEF (�50%), as compared with those with reduced LVEF (<50%), showed significantly highersurvival free from total MACE or VT/VF (log-rank p < 0.001) and significantly smaller LV myocardialdamaged area as evaluated by magnetic resonance imaging (MRI) (p < 0.001). Although CS patients withpreserved LVEF had a good prognosis in general, persistent right ventricular (RV) pacing and reduced EFwere significant predictors for MACE after 1 year from introduction of steroid therapy (hazard ratio, 5.25;95% confidence interval, 1.31–22.50, p = 0.020, hazard ratio, 9.01; 95% confidence interval, 2.45–72.09;p = 0.001). Patients with the 2 factors (LVEF reduction rate >13.9% per year and persistent RV pacing) hadsignificantly higher risk for MACE, compared with those without them (log-rank p < 0.001).Conclusion: The present study demonstrates that CS patients with preserved LVEF have better long-termprognosis than those with reduced LVEF in general. However, we should carefully follow them up, sincechronological reduction in LVEF and persistent RV pacing could predict worse prognosis in those patients.

© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Contents lists available at ScienceDirect

Journal of Cardiology

jo u rn al h om ep age: ww w.els evier .c o m/lo c ate / j j c c

Introduction

Sarcoidosis is a systemic inflammatory disease characterized bynon-caseating granuloma formation. Although sarcoidosis affectsvarious organs, cardiac involvement leads to life-threateningevents, including heart failure and sudden cardiac death due tofatal arrhythmias. Although latest study data demonstrated that

* Corresponding author at: Department of Cardiovascular Medicine, TohokuUniversity Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

E-mail address: vdm@cardio.med.tohoku.ac.jp (M. Nakano).

https://doi.org/10.1016/j.jjcc.2019.04.0160914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights

microRNAs could be one of the novel biomarkers for cardiacsarcoidosis (CS) [1,2], early diagnosis of CS remains a challengingissue. The incidence of CS has been reported to be less than 5%among patients with sarcoidosis, but a post-mortem study hasdemonstrated that cardiac involvement could occur in at least 25%of the patients [3].

Although immunosuppressive therapy with corticosteroids is themainstay of the treatment for CS, angiotensin-converting enzyme(ACE) inhibitors and b-blockers are also used for CS patients withreduced cardiac function. Furthermore, CS patients with high risk forventricular tachyarrhythmias or wide QRS are treated withimplantable cardioverter defibrillator (ICD) and/or cardiac resyn-chronization therapy (CRT) [4]. Advances in diagnostic imaging

reserved.

T. Chiba et al. / Journal of Cardiology 75 (2020) 34–41 35

modality, such as magnetic resonance imaging (MRI) and positronemission tomography (PET), have enabled us to detect CS patientswith preserved left ventricular ejection fraction (LVEF), who haveinflammatory changes and damaged myocardium in the early stageof the disorder [5].

However, clinical course of CS patients with preserved LVEFremains to be fully elucidated. In the present study, we thusexamined the prognosis and risk stratification in CS patients withpreserved LVEF.

Methods

Study population

This study was approved by the University of TohokuInstitutional Review Board (2015-1-152), and all the patients gavetheir informed consent or were informed of the study by postedinformation in our institute. We retrospectively examined91 consecutive patients with CS in our Tohoku University Hospitalfrom October 1998 to December 2015 (age: 57 � 11 years; M/F 25/66). They were classified into 2 groups by LVEF; Group 1 (LVEF�50%, n = 56) and Group 2 (LVEF <50%, n = 35). CS was diagnosedeither by endomyocardial biopsy (histological diagnosis) or clinicalCS manifestations (clinical diagnosis) according to the guidelinesby the Japanese Ministry of Health and Welfare [6]. Implantation ofICD and/or CRT was performed according to the current guidelines[7]. Corticosteroid therapy was administered to all the patients,starting with 30–40 mg/day of prednisone. Doses of prednisonewere decreased by 5 mg every 2 weeks until achieving 20 mg/dayand were then tapered over a period of 6–12 months until themaintenance dose of 5–10 mg/day [8].

Left ventricular function

Left ventricular end-diastolic volume (LVEDV), end-systolicvolume (LVESV), and LVEF were measured by echocardiographyusing the modified Simpson's method. In addition, to assess theimportance of chronological change in LVEF for cardiac events, weexamined reduction rate of LVEF using the following formula:([LVEF on diagnosis] � [LVEF after 1 year from diagnosis]) � 100/LVEF on diagnosis.

Imaging studies

We routinely checked myocardial inflammation in almost allpatients with CS using any or all of imaging studies, including galliumscintigraphy, 18F-fluoro-2-deoxyglucose positron emission tomogra-phy (18F-FDG PET), MRI, and myocardial perfusion scintigraphy(MPS). We evaluated the region of LV myocardial damage using 17-segment model based on the American Society of Nuclear Cardiologyimaging guidelines [9] with 3 imaging modalities except for galliumscintigraphy. FDG PET/computed tomography (CT) scans wereobtained at our institute with a Biograph Duo or a Biograph-40PET/CT scanner (Siemens Medical Solutions, Erlangen, Germany). CSpatients were treated with fasting for 12 h before examination[10]. After approximately 1 h, a spiral CT scan was performed,followed by the collection of PET emission images from the distalfemur to the top of the skull. After approximately 3 h, electrocardio-gram (ECG)-gated spiral CT scan was performed. Positive PET findingwas defined as a focal or focal on diffuse pattern of increased 18F-FDGuptake in the myocardium [11]. 18F-FDG uptake was semi-quantita-tively evaluated with a 5-point grading system as follows: 4+ = verysevere uptake, 3+ = severe uptake, 2+ = moderate uptake, 1+ = milduptake, and 0 = normal [12]. MPS was performed with single photonemission computed tomography (SPECT) using 99mTc-labeled meth-oxy isobutyl-isonitrate (MIBI) or tetrofosmin (TF) as a tracer. The

tracer was injected intravenously at rest, and 60 min later, SPECT datawere acquired using a dual-head gamma camera (Infinia Hawkeye4,GE Healthcare, Chicago, IL, USA) with a high-resolution parallel-holecollimeter. All images were acquired with ECG gating. SPECT imagingdatawereacquiredusinga180� rotationarc,16 framesperheart cycle,and 64 � 64 matrices. Perfusion defect region was defined asdamaged myocardial region due to CS. Myocardial perfusion defectwasalsosemi-quantitativelyevaluatedwith a5-pointgradingsystemas follows: 4+ = very severe defect, 3+ = severe defect, 2+ = moderatedefect,1+ = mild defect, and 0 = normal [12]. Cardiac MRI scans wereperformed by using the standard protocol in our institution and ECG-gatedMRIimageswereobtainedinall patientsduringbreath-holdingon a 1.5-T imager (Magnetom Vision, Siemens Medical Solutions andAchiva, Philips Medical Systems, Best, The Netherlands) using a bodyarray coil (Siemens) or a 5-channel cardiac coil (Philips). Delayedcontrast-enhanced MRI images using inversion recovery-preparedgradient-echo sequence were acquired 10–15 min after injection ofgadopentetate dimeglumine (0.15 mmol/kg) in the same plane ascine imaging with the Siemens Scanner or in 10 horizontal,10 verticallong, and 20 short-axis slices with the Philips scanner. Eachmyocardial segment was scored for the presence of delayedenhancement (DE), a sign of chronic fibrotic change (1 = DE+,0 = DE�).

Definition of events

Ventricular tachycardia and fibrillation (VT/VF) were defined asdocumented VT or VF lasting for >30 s on 12-lead ECG, Holter ECG,or cardiac implantable electronic devices (pacemaker, ICD, or CRT).Heart failure (HF) admission was defined as admission needingsome treatment for HF alone, but not for that to treat arrhythmias.Total major adverse cardiac events (MACE) was defined ascomposite outcome of VT/VF, HF admission, complete atrioven-tricular block (CAVB), and all-cause death.

Statistical analysis

Continuous variables are expressed as the means � SD, andcategorical variables as number and percent. Group comparisonswere performed with Kruskal–Wallis test for multiple continuousvariables and Mann–Whitney U-test. Chi-square test was used forcategorical variables. Univariable and multivariable Cox propor-tional hazard models were applied to examine the associationbetween time to primary outcomes and covariates. To select theoptimal subset of the covariates in the multivariable analysis,stepwise variable selection was adopted. A Kaplan–Meier analysiswas used to assess the time required for the MACE outcome tooccur, and comparison between groups was performed using log-rank tests. Values of p < 0.05 were considered to be statisticallysignificant. All statistical analyses were performed with the use ofJMP software version 12.0 (SAS Institute, Cary, NC, USA).

Results

Patient characteristics

Patient characteristics at baseline are shown in Table 1. Therewas no significant difference in mean age or male sex proportionbetween the two groups. The mean New York Heart Associationclass was significantly lower in group 1 compared with group 2(1.52 � 0.63 vs. 2.11 � 0.83, p < 0.001). Although the prevalence ofextra-cardiac sarcoidosis was comparable between the two groups,the definite histological diagnosis of sarcoidosis was notedmore frequently in group 1 compared with group 2 [38/56(68%) vs. 16/35 (46%), p = 0.037]. b-blockers and ACE inhibitors orangiotensin receptor blockers (ARB) were used in only half of the

Table 1Patient characteristics at baseline.

Patient characteristics Total (N = 91) Group 1 (N = 56) Group 2 (N = 35) p-Value

Male 25 (27%) 13 (23%) 12 (34%) 0.253Age (years) 57 � 11 57 � 11 57 � 10 0.830NYHA class 1.7 � 0.8 1.52 � 0.63 2.11 �0.83 <0.001Hypertension 20 (22%) 14 (25%) 6 (13%) 0.373Dyslipidemia 23 (25%) 14 (25%) 9 (26%) 0.939Diabetes mellitus 14 (15%) 6 (11%) 8 (23%) 0.124Chronic kidney disease 6 (7%) 2 (4%) 4 (11%) 0.199Heart failure 15 (16%) 3 (5%) 12 (34%) <0.001Extracardiac sarcoidosisLung 62 (68%) 40 (71%) 22 (63%) 0.395Eye 34 (37%) 22 (39%) 12 (34%) 0.631Skin 12 (13%) 9 (16%) 3 (9%) 0.291

HistologyPositive histology 54 (59%) 38 (68%) 16 (46%) 0.037Heart 7 (8%) 2 (4%) 5 (14%) 0.103

Medicationb-blockers 54 (61%) 25 (45%) 29 (91%) <0.001ACE-I/ARBs 60 (68%) 34 (61%) 26 (81%) 0.041Amiodarone 21 (24%) 6 (11%) 15 (47%) <0.001Prednisolone 91 (100%) 56 (100%) 35 (100%) 1.000

DevicePacemaker 30 (33%) 23 (41%) 5 (14%) 0.010ICD 9 (10%) 2 (4%) 7 (20%) 0.025CRT 13 (14%) 0 (0%) 13 (37%) <0.001

ECG parameterRBBB 25 (28%) 15 (27%) 10 (29%) 0.893LBBB 1 (1%) 1 (2%) 0 (0%) 1.000RV pacing 29 (32%) 20 (27%) 9 (26%) 0.315NSVT 33 (37%) 13 (24%) 20 (57%) 0.001

Echocardiographic parameterLVEF, % 54 �16 65 � 9 35 � 9 <0.001LVDd, mm 53 � 9 49 � 7 60 � 8 <0.001LVDs, mm 38 � 12 32 � 7 50 � 9 <0.001ESVI, mL/m2 45 � 32 26 � 12 72 � 33 <0.001IVS <8 mm 40 (44%) 17 (30%) 23 (66%) <0.001

Laboratory dataBNP, pg/mL 234 � 419 115 �158 445 � 616 <0.001sIL-2R, U/mL 649 � 495 624 � 445 696 � 586 0.552ACE, IU/L 17 � 9 18 � 10 14 � 8 0.106Cr, mg/dL 0.81 �0.31 0.74 � 0.23 0.92 � 0.39 0.011

Imaging examinationsGa scintigraphy 54 (59%) 32 (57%) 22 (63%) 0.664FDG-PET 79 (87%) 48 (86%) 31 (89%) 0.761Patterns of FDG accumulationFocal 10 (21%) 8 (26%) 0.784Focal on diffuse 13 (27%) 15 (48%) 0.060Diffuse 21 (44%) 7 (23%) 0.091None 4 (8%) 1 (3%) 0.643

SUV max of heart 1.777 2.274 0.080MPS 62 (68%) 35 (63%) 27 (77%) 0.171Perfusion defect (point) 1.074 1.821 <0.001

Cardiac MRI 58 (64%) 39 (70%) 19 (54%) 0.180Delayed enhancement (point) 0.250 0.591 <0.001

Results are presented as either mean � SD or number of patients (%).Maximum of standardized uptake value (SUV max) of heart, perfusion defect, and delayed enhancement are presented as numerics calculated by scoring system.ACE, angiotensin-converting enzyme; ACE-I, angiotensin-converting enzyme inhibitors; ARBs, angiotensin-receptor blockers; BNP, brain natriuretic peptide; Cr, serumcreatinine; CRT, cardiac resynchronization; DE, delayed enhancement; ECG, electrocardiography; ESVI, end-systolic volume index; FDG, fluoro-2-deoxyglucose; Ga,gallium scintigraphy; Hb, hemoglobin; ICD, implantable cardioverter defibrillator; IVS, intraventricular septum; LBBB, left bundle branch block; LVDd, end-diastolic leftventricular dimensions; LVDs, end-systolic left ventricular dimensions; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MPS, myocardialperfusion scintigraphy; NSVT, non-sustained ventricular tachycardia; NYHA, New York Heart Association; PET, positron emission tomography; PM, pacemaker; RBBB,right bundle branch block; RV, right ventricular; sIL-2R, soluble interleukin-2 receptor.We defined RV pacing when (1) there was no own beat in 12-lead electrocardiogram, (2) ratio of pacing with implantable device (pacemaker, ICD, CRT) was over 95%, and(3) there was no biventricular pacing.

T. Chiba et al. / Journal of Cardiology 75 (2020) 34–4136

patients in group 1, whereas they were used in more than 80% ofthe patients in group 2 [b-blockers, 25/56 (45%) vs. 29/35 (91%),p < 0.001; ACE inhibitor/ARB, 34/56 (61%) vs. 26/35 (81%),p = 0.041]. Oral amiodarone was used in �10% of the patients ingroup 1 but was used in �50% of the patients in group 2 [6/56 (11%)vs.15/35 (47%), p < 0.001]. Pacemaker (PM) was implanted to morepatients in group 1 compared with those in group 2, whereasimplantation of ICD and CRT with defibrillator (CRT-D) was less

performed in group 1 compared with group 2 [PM, 23/56 (41%) vs.5/35 (14%), p = 0.010; ICD, 2/56 (4%) vs. 7/35 (20%), p = 0.025; CRT-D, 0/56 (0%) vs. 13/35 (37%), p < 0.001].

Prognosis of CS patients with or without preserved LVEF

During a mean follow-up of 84 months, total MACE and VT/VFoccurred in a significant higher percentage of patients in group 2 as

Fig. 1. Kaplan–Meier analysis of total and each MACE in cardiac sarcoidosis patientsin group 1 (LVEF �50%) and group 2 (LVEF <50%). Total MACE, (B) VT/VF, and (C) HFadmission. HF, heart failure; LVEF, left ventricular ejection fraction; MACE, majoradverse cardiac events; VT, ventricular tachycardia; VF, ventricular fibrillation.

T. Chiba et al. / Journal of Cardiology 75 (2020) 34–41 37

compared with group 1 [24 (69%) vs. 11 (20%), (log-rank p < 0.001),and20 (57%) vs. 7 (13%), (log-rank p < 0.001), respectively] (Fig.1A andB). Similarly, HF admission occurred in a higher percentage of patientsin group 2 as compared with group 1 [7 (20%) vs. 5 (9%)] (log-rankp = 0.067) (Fig. 1C). Four patients showed de novo CAVB (1 in group 1,and3ingroup2),and4otherpatientsdiedingroups1and2(1ingroup1, and 3 in group 2). The cause of death included circulatory failure,sudden death, esophageal cancer, and natural disaster.

At diagnosis of CS, 29 patients had RV pacing [20 in group 1(36%), 9 in group 2 (26%)]. We examined atrioventricular (AV)conduction of the patients with steroid therapy at 1 year after CS

diagnosis in both groups (Fig. 2). Although the number of patientswith improved AV conduction was 12 (60%) in group 1, no patientsshowed improvement of AV conduction in group 2. On the otherhand, one patient showed de novo AV block in group 1 (2%), and 3(9%) in group 2. In the imaging examinations, FDG-PET showed that18F-FDG uptake tended to be larger in group 2 than in group 1 intotal LV (p = 0.080) (Fig. 3A). Furthermore, MPS and MRI showedthat the extent of positive area was larger in group 2 than in group1 (MPS, p = 0.007; MRI, p < 0.001), suggesting that group 2 hadmore advanced myocardial damage compared with group 1(Fig. 3B and C).

Prognosis and risk stratification of CS patients with preserved LVEF

Although group 1 showed better prognosis than group 2 as awhole group, some patients in group 1 also experienced MACE. Werecently reported that CS patients tend to experience ventriculartachyarrhythmias more frequently within 1 year after introductionof steroid therapy than after 1 year [13]. Thus, we next examinedthe time-course and risk factors of MACE in CS patients in group1. Within 1 year after introduction of steroid therapy, 4 out of 56 CSpatients in group 1 (7%) experienced MACE (4 patients experiencedVT/VF and no patients experienced HF admission, AVB, or death).On the other hand, 9 (16%) had MACE (VT/VF in 5, HF admission in5, de novo CAVB in 1, and death in 1) after 1 year.

Although univariable Cox proportional-hazards analysisshowed that MACE (all VT/VF) within 1 year after introductionof steroid therapy was significantly associated with dyslipidemia,diabetes mellitus, right bundle branch block, and non-sustainedVT, multivariable analysis showed that these associations were notsignificant (Supplement Table 1).

Next, we quantified the reduction rate of LVEF and LVEF at 1 yearafter steroid introduction to detect patients at high risk of MACE,VT/VF, and HF admission after 1 year of steroid therapy usingreceiver-operator characteristic (ROC) curve analysis, whichshowed that cut-off values for MACE, VT/VF, and HF admissionwere reduction rate in LVEF at 1 year >13.9% per year each and that<56%, 46%, and 45%, respectively (Fig. 4A and B, Supplement Fig.1Aand B, Supplement Fig. 2A and B).

Cox proportional-hazards analysis showed that the occurrenceof total MACE after 1 year of steroid therapy was not associatedwith LVEF after 1 year from steroid introduction (hazard ratio,1.33; 95% confidence interval, 0.21–12.00; p = 0.775), butsignificantly associated with persistent RV pacing (hazard ratio,4.68; 95% confidence interval, 1.07–24.58; p = 0.040) and LVEFreduction rate >13.9% per year (hazard ratio, 8.17; 95% confidenceinterval, 1.22–85.02; p = 0.029) (Table 2). We examined theclinical features of the CS patients with worsening LVEF(reduction rate >13.9% per year) in SupplementTable 2. Furthermore, we have performed univariable andmultivariable Cox proportional-hazards analysis (SupplementTable 3), demonstrating that there was no significant risk factorassociated with LVEF worsening. Furthermore, we examined therelationships between MACE and 2 correlated factors (LVEFreduction rate >13.9% per year and persistence of RV pacing).Event-free survival from MACE showed that patients with bothgreater LVEF reduction rate (>13.9% per year) and persistent RVpacing had significantly higher risk of MACE compared with thosewithout them (log-rank p < 0.001) (Supplement Fig. 3).

Although univariable analysis showed that VT/VF after 1 year ofsteroid therapy was associated with positive histology, diabetesmellitus, thin intraventricular septum on ultrasound cardiography(UCG), and positive gallium-scintigraphy, multivariable analysisshowed no significant association between these parameters andVT/VF (Supplement Table 4). Similarly, univariable analysisshowed that HF admission after 1 year of steroid therapy was

Fig. 2. Number of patients with RV pacing at CS diagnosis and one year after CS diagnosis. AV, atrioventricular; CS, cardiac sarcoidosis; RV, right ventricular.

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associated with New York Heart Association class, positivehistology, LVEF reduction rate >13.9% per year, and BNP levels,however, multivariable analysis showed no significant associationbetween these parameters and HF admission (Supplement Table 5).

Discussion

The novel findings of the present study were as follows: (1)prognosis of CS patients was strongly correlated with LVEF atdiagnosis, in association with the extent of myocardial damage asevaluated by reduced myocardial perfusion on MPS and/or delayedenhancement on MRI, even if they were treated with immuno-suppressive therapy and modern cardiac devices, such as ICD andCRT-D. (2) Although CS patients with preserved LVEF generally hadbetter prognosis, some of them experienced adverse clinicalevents, which could be predicted by worsening of LVEF (reductionrate >13.9% per year) and persistent RV pacing despite steroidtherapy. To the best of our knowledge, this is the first study thatdemonstrates the prognosis and risk factors of CS patients withpreserved LVEF.

Prognosis of CS patients with or without preserved LVEF

It is widely known that reduced LVEF is associated with poorprognosis in patients with chronic HF in general. It has also beenreported that CS patients with reduced LVEF at diagnosis areresistant to HF therapy [14]. Since VT/VF are one of the majorcauses of death in CS patients, the previous studies examined therelationship between clinical characteristics and occurrence ofventricular arrhythmias [4]. However, since HF is also one of theimportant adverse cardiac events in CS patients in addition to VT/VF [14], we examined total MACE including HF admission in CSpatients in the present study.

The present study demonstrates that CS patients with reducedLVEF (<50%), which was associated with more myocardial damage

on MRI, had more occurrence of total MACE and fatal ventriculararrhythmias compared with those with preserved LVEF (EF > 50%).Myocardium with delayed enhanced area on MRI reflects advanceddamaged lesion, such as scar tissue, which could be a substrate oftachyarrhythmias [5]. Moreover, reduced LVEF usually causesmyocardial remodeling including electrophysiological and me-chanical myocardial changes, such as down- or up-regulation ofion channels and increment of fibrosis, which cause shortening ofrefractory periods and slow conduction area with resultantoccurrence of tachyarrhythmias [15,16]. In contrast, in the presentstudy, no significant difference was noted in the occurrence of HFadmission between the two groups. This was probably because CSpatients with reduced LVEF were more likely to receive b-blockersand ACE inhibitors/ARBs than those with preserved LVEF.

Early immunosuppressive therapy may be effective for certainCS patients with AV block [17]. Although, it was also reported thatpatients with high-degree AV block at diagnosis of CS had a higherrate of subsequent fatal cardiac events despite immunosuppressivetherapy [18], clinical characteristics and risk stratification of thesepatients remains to be fully elucidated. Therefore, in the presentstudy, we also examined the relationship of LVEF and improvementin AV block after steroid therapy, demonstrating that LVEF atdiagnosis was associated with improvement in AV block. Thus, CSpatients with reduced LVEF and AV block may be good candidatesfor CRT, even if they have slightly reduced cardiac function (LVEF35–50%), as indicated by the recent guidelines [19].

Time course and risk stratification of CS patients with preserved LVEF

Although reduced LVEF would be known as one of the poorprognostic markers in CS patients, recent studies reported thatsome CS patients with delayed enhancement on MRI had pooroutcomes in spite of preserved LVEF [20,21]. The present study alsoshowed that although CS patients with preserved LVEF generallyhad better prognosis than those with reduced LVEF, some of them

Fig. 3. Multi-modality evaluation of LV myocardial damage in cardiac sarcoidosispatients. (A) FDG-PET, (B) MPS, and (C) MRI. FDG-PET, 18F-fluoro-2-deoxyglucosepositron emission tomography; LV, left ventricular; MPS, myocardial perfusionscintigraphy; MRI, magnetic resonance imaging.

Fig. 4. The receiver-operator characteristic curve in conjunction with LVEF and totalmajor adverse cardiac events after one year after cardiac sarcoidosis diagnosis. (A)LVEF at one year after steroid introduction. (B) Reduction rate of LVEF. AUC, areaunder the curve; LVEF, left ventricular ejection fraction.

T. Chiba et al. / Journal of Cardiology 75 (2020) 34–41 39

also experienced adverse cardiac events. Recently, we reportedthat CS patients are likely to experience more ventriculartachyarrhythmic events within 1 year of steroid therapy, whenassociated with reduced LVEF and positive gallium-scintigraphy[13]. However, time-course and risk stratification of CS patientswith preserved LVEF remains to be fully examined [20]. Thus, in thepresent study, we examined the occurrence of MACE and its riskfactors within or after 1 year of steroid therapy separately. Thepresent results showed that VT/VF were major contents of MACEwithin 1 year from introduction of steroid therapy in CS patientswith preserved LVEF. This result was coincident with our previousreport and others, suggesting that inflammatory conditions bysteroid therapy may be involved [22–25]. Since multivariableanalysis showed no specific risk factors for predicting VT/VF in this

phase, it is conceivable that inflammatory responses are involvedin VT/VF occurrence more than baseline characteristics of thepatients. The present results also showed that MACE after 1 year ofsteroid therapy were VT/VF and HF admission in CS patients withpreserved LVEF, in association with LVEF reduction rate >13.9% peryear. This was probably because progression of LV remodeling andresultant scar formation were involved in the occurrence of HFadmission and fatal ventricular arrhythmic events [26].

The present study also demonstrates that persistent RVpacing is an independent predictor for MACE occurrence.Persistent RV pacing is known to worsen LV function [27],which could also contribute to occurrence of HF admission andVT/VF. Moreover, among CS patients with preserved LVEF, thosewith both factors (LVEF reduction rate >13.9% per year andpersistent RV pacing) had a higher risk of total MACE, as in thecase with CS patients with reduced LVEF. Thus, we should payattention to CS patients regardless of LVEF at diagnosis,especially to those with LVEF deterioration and persistent RVpacing despite steroid therapy.

Table 2Cox proportional-hazards analysis for correlation with total MACE after one yearfrom CS diagnosis.

Variable HR (95% CI) p-Value

Univariable analysisMale 1.03 (0.15–4.25) 0.975Age (years) 19.87 (0.96–719.72) 0.054NYHA class 3.74 (0.51–24.01) 0.185Hypertension 1.18 (0.28–7.94) 0.833Dyslipidemia 4.59 (1.21–18.66) 0.026Diabetes mellitus 5.34 (1.12–20.33) 0.037Chronic kidney disease 5.87 (0.31–33.35) 0.182Extracardiac sarcoidosisLung 1.47 (0.31–5.61) 0.594Eye 1.51 (0.39–7.28) 0.563Skin 1.44 (0.21–5.99) 0.660

HistologyPositive histologya . . . . . .

Medicationb-blockers 1.07 (0.27–4.06) 0.915ACE-I/ARBs 0.64 (0.16–2.60) 0.510Amiodarone 5.09 (1.07–19.38) 0.042

ECG parameterRBBB 1.43 (0.30–5.42) 0.624NSVT 3.03 (0.75–11.50) 0.114RV pacing (1 year) 7.81 (2.05–31.74) 0.003

Echocardiographic parameterLVEF at 1year after CS diagnosis 7.89 (1.91–53.06) 0.004LVEF reduction rate >13.9% per year 13.72 (3.30–92.35) <0.001IVS <8 mm 4.95 (1.29–23.60) 0.020

Laboratory dataBNP 6.70 (0.68–37.68) 0.094Cr 10.63 (0.67–93.59) 0.087

Imaging examinationsGa scintigraphy; positive+ 9.67 (1.54–186.17) 0.014FDG-PET; uptake+ 2.13 (0.40–15.65) 0.378MPS: defect+ 1.13 (0.22–8.15) 0.892Cardiac MRI: DE+a . . . . . .

Multivariable analysisRV pacing (1 year) 4.68 (1.07–24.58) 0.040LVEF reduction rate >13.9% per year 8.17 (1.22–85.02) 0.029

Results are presented as either mean � SD or number of patients (%).ACE-I, angiotensin converting enzyme inhibitor; ARBs, angiotensin-receptorblockers; BNP, brain natriuretic peptide; CI, confidence interval; Cr, serumcreatinine; CS, cardiac sarcoidosis; DE, delayed enhancement; ECG, electrocar-diography; FDG, fluoro-2-deoxyglucose; Ga, gallium scintigraphy; HR, hazardratio; IVS, intraventricular septum; LVEF, left ventricular ejection fraction;MACE, major adverse cardiac event; MRI, magnetic resonance imaging; MPS,myocardial perfusion scintigraphy; NSVT, non-sustained ventricular tachycar-dia; NYHA, New York Heart Association; PET, positron emission tomography;RBBB, right bundle branch block; RV pacing (1 year), Persistent RV pacing after1 year of steroid therapy; sIL-2R, soluble interleukin-2 receptor.a Estimation procedure was not converged.

T. Chiba et al. / Journal of Cardiology 75 (2020) 34–4140

Roles of imaging modality for detecting myocardial damage in CSpatients

PET is one of the useful diagnostic tools unmasking myocardialinflammation in CS patients [28]. However, in the present study, PEThad no power to correlate LVEF in CS patients, whereas MRI and MPScould detect larger myocardial damage in relation to LVEF reductionrate inCSpatients. Thisdiscrepancyamong imagingmodalitiescouldbe explained as follows: PET can detect inflammatory myocardiumthat could be curable with steroid therapy, whereasMRI and MPS candetect more damaged tissue, such as scar, which could not be curablewith steroid therapy. Thus, the findings of irreversible myocardialdamage on MRI or MPS could well correlate to cardiac function (e.g.LVEF) in CS patients [5,29].

Study limitations

Several limitations should be mentioned for the present study.First, the tapering protocol of steroid therapy and adjustment of

maintenance dose were entrusted to each physician's decision.However, almost all patients received the same protocol forintroduction of steroid therapy and reached the maintenance dosein one year. Second, in the present study, imaging examinationswere not performed uniformly in all the patients. MPS and PETwere often performed at the same time in many patients, but MRIwas not performed in the patients with device therapy. In addition,imaging examinations at 1 year after diagnosis of CS were notperformed in all patients depending on physician's decision. Third,since the PET examination was performed before introduction ofthe current guidelines in most cases, dietary modification (e.g.carbohydrate restriction) was not complete [10]. Fourth, thenumber of CS patients with RV pacing was small. Thus, we wereunable to exclude the possibility that RV pacing contributed to thechronological reduction in LVEF. Fifth, we also were unable toexclude the possibility that relapse of active sarcoid inflammationplayed some roles in the chronological reduction in LVEF. Sixth,because this study is a retrospective analysis, the present resultsneed to be confirmed by prospective study. Seventh, we wereunable to fully evaluate the effectiveness of steroid therapy forinflammation status of CS patients because the number of CSpatients with follow-up imaging studies was limited. Eighth, sincewe examined CS patients with preserved LVEF, we consider thatthe extents of inflammation and myocardial damage were too mildto play a prognostic role in our patients as compared with CSpatients in other studies.

Conclusion

The present study demonstrates that CS patients withpreserved LVEF have better long-term prognosis than those withreduced LVEF in general. However, we should carefully follow themup, since chronological reduction in LVEF and persistent RV pacingcould predict worse prognosis in those patients.

Conflict of interest

The authors have no conflict of interest to disclose.

Acknowledgments

We thank Satoshi Miyata for contribution to statistical analysis.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.jjcc.2019.04.016.

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